Colorectal cancer is the third leading cause of cancer-related deaths in the United States with 130,000 new cases diagnosed per year and approximately 57,000 deaths estimated in 2003 secondary to this disease. Despite improvements in surgical resection and multimodality therapy, approximately 50% of patients with colorectal cancer will succumb to their disease. A better understanding of the signaling pathways contributing to colorectal cancer proliferation and metastasis will provide targets for novel therapeutic agents and drug delivery methods and further enhance patient survival. Our laboratory is specifically focused on the signaling pathways contributing to gastrointestinal (GI) cancer as well as normal mucosal proliferation. Recently, we have shown that inhibition of phosphatidylinositol-3 kinase (PI3K) enhances intestinal cell differentiation and stimulates expression of downstream target genes that are important for differentiation and apoptosis. Furthermore, we have shown that inhibition of PI3K enhances sodium butyrate (NaBT)-mediated apoptosis and decreases viability and growth of human colon cancers both in vitro and in vivo. Therefore, the central hypothesis of this proposal is that colon cancer growth and tumor progression are augmented by increased PI3K activity; the inhibition of PI3K can inhibit tumor growth, and, moreover, can sensitize colorectal cancers to chemotherapeutic agents. The long-term goal of this proposal is to identify specific molecular targets for the treatment of colorectal cancer. To examine our hypothesis and address the long-term goal, we have designed experiments with the following Specific Aims: 1) To further define the localization of expression patterns of PI3K and downstream effector proteins in colon cancers and surrounding stroma. For these studies, we will further analyze expression patterns of PI3K/Akt and downstream effector proteins in colorectal cancers as well as surrounding stroma. In addition, we will determine when PI3K activity is increased in relation to cancer development, and finally, we will assess the proteomic profile of colorectal cancers and surrounding stromal tissue. 2) To determine the contribution of tumor stromal cells on PI3K/Akt signaling in colon cancers. We will determine the contribution of surrounding stromal tissue on PI3K/Akt signaling to colon cancers and specifically assess tumor-associated fibroblasts with respect to PI3K signaling. 3) To assess novel strategies of PI3K/Akt inhibition on in vivo tumor growth and metastasis. Using models of colorectal cancer metastasis, we will determine the effectiveness of PI3K/Akt inhibition on tumor growth. Finally, we will utilize novel techniques of drug delivery to determine whether enhanced delivery of the PI3K/Akt inhibitors can further augment tumor inhibition and provide a more selective method of treating colorectal cancers. Ultimately, the cumulative information derived from these studies will lead to better targeted therapies and treatment paradigms for colorectal cancer.